Abstract Objective: The objective of the study was to assess the efficacy and safety of subcutaneously (SC) and intramuscularly (IM) administered BT088 (Fovepta) human hepatitis B immunoglobulin in neonates of hepatitis B surface antigen (HBs/HBsAg)-positive mothers in the prevention of hepatitis B infection. Methods: This was an open, prospective, multicenter trial, in which infants were randomized to receive a single SC or IM dose of BT088 (200 IU, 0.4 mL) within 12 h of birth simultaneously with active vaccination against hepatitis B. The primary efficacy variable was the response rate, defined as the proportion of infants whose anti-HBs concentration was negative at predose and ≥100 IU/L 48 to 72 h postdose. Results: The full analysis set included 31 neonates (17 SC and 14 IM). Response was experienced by 30 (96.8%) of 31 infants who received BT088 by either route of administration. The median postdose anti-HBs concentration was 261.2 IU/L. One neonate had a postdose anti-HBs level lower than 100 IU/L (81.0 IU/L). No infant experienced seroconversion during the 7- to 15-month follow-up. BT088 was well tolerated, with no allergic-like, or injection-site reactions observed. Conclusion: SC and IM administration of 200 IU (0.4 mL) BT088 resulted in protective serum anti-HBs titers within 72 h of administration in newborn infants and was well tolerated and effective.